N-benzyl-N-{8 2-phenyl-2-(4-phenyl-1-piperidyl)-ethyl{9 -propionamide para-chlorobenzene sulfonate

ABSTRACT

N-benzyl-N-(2-phenyl-2-(4-phenyl-1-piperidyl)ethyl)propionamide p-chlorobenzenesulfonate has effectiveness comparable to methadone in suppressing narcotic withdrawal symptoms and in maintenance therapy of narcotic addicted laboratory mammals.

United States Patent [1 1 Havera [4 1 Sept. 16, 1975 N-BENZYL-N-[2-PHENYL-2-(4-PHENYL-1- PIPERIDYL)-ETHYLl-PROPIONAMIDE PARA-CHLOROBENZENE SULFONATE [75] Inventor: Herbert John Havera, Edwardsburg,

Mich.

[73] Assignee: Miles Laboratories, Inc., Elkhart,

Ind.

[22] Filed: Apr. 3, 1974 211 Appl. No.: 457,456

Related US. Application Data [62] Division of Ser. No. 363,425, May 24, 1973.

[52] US. Cl. 424/267 [51] Int. Cl. A61K 31/445 [58] Field of Search 424/267 [56] References Cited UNITED STATES PATENTS 3,518,274 6/1970 Stryckcr 424/267 3,773,955 1 H1973 Pacter et a1 424/260 Primary Examiner-Albert T. Meyers Assistant Examiner-Norman A. Drezin Attorney, Agent, or Firm-Myron B. Sokolowski 1 Claim, No Drawings 1 N-BENZYL-N-[2-PHENYL-2-(4-PHENYL-l- PlPERlDYL)-ETHYL]-PROPIONAMIDE PARA-CHLOROBENZENE SULFONATE This is a division of application Ser. No. 363,425, filed May 24, 1973.

BACKGROUND OF THE INVENTION 1. Field of the Invention Treatment of narcotic addiction currently involves two overlapping aspects and objectives: withdrawal of the narcotic and rehabilitation of the addict. In the case of opioid dependence, specifically heroin or morphine addiction, the treatment of withdrawal symptoms and rehabilitation merge in the concept of maintenance therapy.

Maintenance therapy is a relatively new approach to narcotic addiction pioneered predominantly by Dole and co-workers (Arch. Int. Med., 118: 304 [1966]; J. Am. Med. Assn., 206: 2708 [I968]; and New Engl. J. Med., 280: 1372 [1969]). The therapeutic regimen devised by Dole et al. involves stabilization of narcotic addicts by the oral administration of a narcotic substitute so that the euphoric effects of even high doses of intravenously administered narcotics are obviated. Oral ad ministration of the narcotic substitute is of central importance to maintenance therapy because the psychological extremes which characterize effects of repeated intravenously administered narcotics are eliminated. Oral ingestion of the narcotic substitute also facilitates supervision of administration, thus minimizing the possibility of illicit redistribution of the substitute.

The narcotic substitute most frequently utilized in maintenance therapy is methadone hydrochloride (hereinafter referred to as methadone). Although the use of methadone as a narcotic substitute in maintenance therapy has been relatively successful, it is potentially subject to abuse if administered intravenously to obtain potentiated narcotic effects.

This invention provides a possible candidate for the suppression of withdrawal effects of narcotics and for the maintenance therapy of addiction which is effective only upon oral administration.

2. Description of the Prior Art Bochmuhl et al. reported the synthesis and structure of methadone, 6-dimethylamino-4,4-diphenyl-3- heptanone (Ann., 561: 52 [1948]). As is evident from its structure,

QJH -NH CI-CO-Cl-l-Cl SUMMARY OF THE INVENTION This invention comprises: l the compound N- benzyl -N-[ 2-phenyl-2-(4-phenyll -piperidyl )ethyl]- propionamide p-chlorobenzenesulfonate; (2) its total synthesis; and (3) its utility in the treatment of narcotic abstinence symptoms or in the maintenance treatment of narcotic addicted experimental animals.

N-ben2yl-N-[2-phenyl-2-( 4-phenyll piperidyl)ethyl]propionamide p-chlorobenzenesulfonate (hereinafter referred to as TR 2923) has the following structural formula:

One of the physical chemical properties of TR 2923 which is germane to its utility is its virtual insolubility in water (less than 0.05%).

Example 1 of the Description of Preferred Embodiments section of this specification delineates the total synthesis of TR 2923, which is a modification of the method disclosed by W.G. Strycker in US. Pat. No. 3,518,274 (issued June 30, 1970). For purposes of this section, the following sequence of reactions represents a compendium of this synthesis:

NaOl-l benzene;

-Continucd I Na CO Q'CHZ-NH-CO-CHZ-CI OPL LiAlH benzene In contrast to its congeners, TR 2923, when adminisstirred solution of benzylamine (64.4 g, 0.6 mole) in tered orally, exhibits unexpected utility in suppression 650 ml of benzene and 200 ml of NaOH. This mixof narcotic withdrawal (or abstinence) symptoms and ture was stirred in the cold for an additional hour and in model maintenance therapy of narcotic addicted exsubsequently filtered. The solid obtained from the conperimental animals. Example 2 of the Description of centration of the filtrate was recrystallized from an Preferred Embodiments section of this specification aqueous methyl alcohol: yield, 145 g; m.p. 96.597.0. outlines detailed results of the comparable effective- Analysis.

ness of TR 2923 to the reference drug methadone in Calculated; CHHHCINO; N, 539

suppressing naloxone-precipitated abstinence symp- Found; N,

toms in narcotic addicted rats. Example 2 also demon- B. 2 p 1 2 4 p 1 1 p Acetstrates the utility of TR 2923 as a possible alternate to amide methadone in the maintenance therapy of narcotic ad- A mixture ofN benzyl a chlorophenylacetamide (62 diction. For purposes of definition, the term mainteg 0239 mole) 4 phenylpiperidine (385 g, 0239 nance therapy refers to the therapeutic concept and mole), sodium carbonate (2&6 g, 027 mole) and 350 regimeh dfiveloped by Dole and co'workers (See refer ml of dimethylformamide was heated under reflux with ehces Cited in Field of the Invention, pra). stirring for 20 hours. The mixture was filtered. The fil- Like methadone, TR 2923 is effective when Orally 40 trate was diluted with methyl alcohol and water, then administered; unlike methadone, however TR 2923 cooled. The solid that formed was collected and dried:

cannot be administered intravenously because of its inyield, 732 133 134 soluble character. As a potential alternate to metha- A l i done in maintenance treatment of narcotic addicts, TR C l -m d; C i-[ 10 0; N, 7,29

2923 possesses the additional advantage that it cannot F d; N,7,42 Y be abused by intravenous self-administration to obtain C, N-[2-Phenyl-2-(4-Phenyl-1-Piperidyl)Ethyl]Benpotentiated effects. In Example 2, TR 2923 was susl i pended in 20% (W/V) mucilage of acacia. Alternately A t t h d f (THF) Solution f 1 -2- it can be mixed with a chocolate paste, or with other phenyl-2-(4-phenyl-l-piperidyl)acetamide (73 g, 0.19 Preparations for Oral ingestion mole) was slowly added to a stirred suspension of This invention, accordingly, has the following ob- LiA|H4 11 g, 02 5 mole) in 150 m] f and the Jectsi mixture was heated under reflux for 16 hours. The to Provide a o p which Suppresses narcotic cooled mixture was reacted with l 1 ml of water in 100 withdrawal symptoms in narcotic addiction; 1 f (dmpwise) f ll d by 1 m] f 20% to P p a 9 Ph which is a Potential r- NaOH, and 33 ml of water. The mixture was filtered nate t0 methad ne m malnt a h r py of nafCOtlC and the filtrate was concentrated and distilled: b.p.,

addiction; and 2lO-2l8; yield, 46 g.

3. to furnish a compound which has the above objects Analysis, and which additionally can be administered only orally. calculat'ed C2 H30Nl N 7 56 6 DESCRIPTION OF THE PREFERRED Foundi N,

EMBODIMENTS D. N-Benzyl-N -[2-Phenyl-2-(4-Phenyl-l-Piperidyl)E- EXAMPLE I thyl]Prop1onam1de y o To 48 g (0.13 mole) of N[2-phenyl-2-(4-phenyl-lpiperidyl)ethyl]benzylam|de m ml of dry benzene N'BenzyliN'[Z'PhenyIQ'M'PhenYI'LPpendyUE' was added 17.0 g (0.13 mole) of propionic anhy-dride. thyuproplonamlde Para'Chlorobenzenesulfonate The reaction mixture was heated at reflux for 2 hours.

A. N-Benzyl-a-Chlorophenylacetamide The solution was treated with 200 ml of 10% NaOH A benzene solution of a-chlorophenylacetyl chloride and then washed with water. The organic layer was (1 13.5 g, 0.6 mole) was slowly added to an ice-cold, dried over MgSO and concentrated in vacuo giving an hol and ether: yield, 1.2 g,m.p. 155-157", solubility 5.2 X l"-% in water.

Analysis: Calculated: C;; H ,ClN,O S: C, 67.89; H, 6.35; .N,

Found: C. 68.39; H, 6.47; N, 4.28.

EXAMPLE 2 Comparative Effectiveness of Orally Administered Doses of N-Benzyl-N-[2-Phenyl-2-(4-Phenyl-l-Piperidyl)- EthyllPropionamide Para-Chlorobenzenesulfonate' (TR 2923) and Methadone in Suppressing Narcotic Withdrawal Effects and in Maintenance Therapy of Morphine Addicted Rats It has been demonstrated that narcotic addiction sure to morphine (Greenbach, Fed. Proc., 28: 262 [1969]), and that thedegree of this addiction can be assessed by the intensityof abstinence symptoms or by the dose of naloxone required to precipitate such symptoms (Way et al.. Science; 162: i290 [1968]). Abstinence effects or withdrawal symptoms in morphine addicted rats include diarrhea. irritability to handling, chewing. withdrawal jumping. and teeth chattering. A rapid test for the action of drugs on addiction in the rat. utilized in this Example.- involves induction of addiction with a single subcutaneous dose of 150 mg/kg of morphine in a sustained release suspension and, 24 hours later, precipitation of withdrawal effects by administration of a subcutaneous dose of naloxone of L0 mg/kg (H.O..l Collier, et 'al., Nature: 237.220 [I972]. To compare the effects of TR 2923 and methadone in naloxone precipitated withdrawal symptoms. varying doses of either drug were orally administered to the rats.

Methadone HCl or TR 2923 was administered orally in distilled water or a suspension of W/v mucilage of acacia, respectively.

Tables I and ll summarize the results of suppression by oral methadone HCl or TR 2923 of naloxone- 5 precipitated morphine withdrawal symptoms in the morphine addicted rat. The numerator represents the number of rats in which a given symptom was observed while the denominator denotes the population of rats quickly can be induced in the rat by continuous expoinvolved.

TABLE 1 Drug Treatment Dose in mg No. of Deaths Incidence of Withdrawal Effect 1 h Prior to Base/kg Prior to in Morphine-Dependent Rats Naloxone P.O. Naloxone I Diarrhea irritability Chewing by Min. to Handling Distilled 0/6 6/6 4/6 6/6 water Methadone 40 I /5 3/4 2/4 l/4" HCl 80 H6 0/5" 0/5 l/5 I 4/5 0/l 0/l Oll Acacia 0/8 7/8 7/8 4/8 TR 2923 40 O/S 7/8 7/8 3/8 80 1/6 5/5 3/5 2/5 I60 1/8 5/7 1/7 2/7 Nuloxune was given at I In; base/kg S.C. Indicates significant (P 0.05) of w effect r to TABLE ll Drug Dose in No. of Percentage Incidence of Withdrawal Effect Treatment mg base/kg Deaths in Morphine-Dependent Rats l h, Prior P.O. Prior to to Naloxone Naloxone Jumping Diarrhea lrritubility Chewing Teeth by 15 Min. to touch to handling Chattering Distilled 0/9 78 78 44 100 I00 I00 water Methadone 40 O/ I0 30 0* 0* 40" 5O 40* HCI 80 3/l0 0* 0" 0* 14* 14* 0- 160 5110 0" 0 0 20 40" 0" Acacia a 0/l2 83 I00 8 I00 I00 TR 2923 40 2/9 78 78 l l 78 I00 I00 3/l2 S6 67 ll 67 I00 I00 I60 2/l2 40 40* 0 20 9O Indicates significant (P 0.05) suppression of withdrawal effect compared to controls.

Naloxunc was given at 1 mg base/kg S.C.

- EXAMPLE 3 Suppression of Heroin-Seeking hi Heroin-Addicted Rats Heroin dependence, was induced in two female-W tar rats by the method described by Collier-(Endeavor,

31: 123 [1972]). In the latter procedure the rats were 1 I:

prepared with an indwelling intrave n'ous cannula com nected to an infusion pump which was activated by a lever in the wall of a cage containing the 'rats.- Byapressing the lever, the rats self-injected ,thcheroin. i.

The rats had reached a stable level of self;-

administration of heroin over a 2 week period (0.25, mg/kg infusion of heroin at aerate of 0.1 ml/lO sec); Duringthis period the rats were fed chocolate paste" (:3 r g/rat) daily at noon; .Food pellets were also available ad lib.

Once the rats became dependent on heroin, they were offered TR 2923 in chocolate paste in three dose levels: 10, 40 and 80 mg/kg; and each treatment day was separated by two days during which chocolate paste alone was available. Over the'24 hour periodfol 'piioi to or'altreiitmentxThis' r'e'lapse did not occur until t'h e 28 3i) hour period in'the other animal. Behavioral spectivelyr Dur ing theiperi0d20-24 hours after oral'administration of BO mg/kgof TR 2923;one animal began self-administration of heroin at a'rate equivalent to that effects after administration of TR 2923 in both rats were similar to tho se seen after heroin.

l. A method of suppressing narcotic abstinencesymptoms in maint 'enance tlierapy of a narcotic addicted mammal comprising:

orally administering to said mammal an effective amount of -i N+benzyl N-[ 2-plienyl-2-(4-phenyl-lpipcridyl )ethyl]propionamide p-chlorobenzenesulfonatef.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,906,100

DATED September 16, 1975 INVENTOR(S) Herbert John Havera It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown be ow:

Columns 3 E 4, before line 23, insert the following 2 lines of drawings:

G1 I COC H 2 5 CH OH CH NH-CH CH-N 9 O Cl fOC H V 0 so H Signed and Scaled this Eighth Day of March 1977 Q [SEAL] Arrest:

RUTH c. MASON c. MARSHALL DANN Arresting Officer Commissioner njParems and Trademark: 

1. A METHOD OF SUPPERESSING NARCOTIC ABSTINENCE SYMPTOMS IN MAINTENANCE THERAPY OF A NARCOTIC ADDICTED MAMMAL COMPRISING: ORALLY ADMINISTRATING TO SAID MAMMAL AN EFFECTIVE AMOUNT OF N-BENZYL-N-(2-PHENYL-2-(4-PHENYL-1-PIPERIDY) ETHYL)PROPIONAMIDE P-CHLOROBENZENEUSLFONATE. 